The present invention generally relates to methods and/or systems for precisely controlling and measuring heating. More particularly, the present invention provides a technique, including methods and devices, for providing and controlling heat to samples in a channel of a micro scale sample handling system. Merely by way of example, the invention is applied to a polymerase chain reaction process, commonly termed PCR, performed in a microfluidic system or device but it will be recognized that the invention has a much wider range of applicability. The invention according to further embodiments also provides techniques for monitoring and controlling a variety of process parameters using impedance and/or conductance measurements.
According to further embodiments, the invention relates to a computer method and/or system for precisely determining temperature and/or controlling heating in specific devices.
The discussion of any work, publications, sales, or activity anywhere in this submission, including in any documents submitted with this application, shall not be taken as an admission by the inventors that any such work constitutes prior art. The discussion of any activity, work, or publication herein is not an admission that such activity, work, or publication existed or was known in any particular jurisdiction.
There has been a growing interest in the manufacture and use of microscale systems for the acquisition of chemical and biochemical information. Techniques commonly associated with the semiconductor electronics industry, such as photolithography, wet chemical etching, etc., are being used in the fabrication of microscale systems, such as microfluidic systems. The term xe2x80x9cmicrofluidicxe2x80x9d refers generally to a system or device or xe2x80x9cchipxe2x80x9d having channels and chambers which are generally fabricated at the micron or submicron scale, e.g., having at least one cross-sectional dimension in the range of from about 0.1 xcexcm to about 500 xcexcm. Early discussions of the use of planar chip technology for the fabrication of microfluidic systems are provided in Manz et al., Trends in Anal. Chem. (1990) 10(5):144-149 and Manz et al., Adv. in Chromatog. (1993) 33:1-66, which describe the fabrication of such fluidic devices and particularly microcapillary devices, in silicon and glass substrates.
Applications of microscale and/or microfluidic systems are myriad. For example, International Patent Appln. WO 96/04547, published Feb. 15, 1996, describes the use of microfluidic systems for capillary electrophoresis, liquid chromatography, flow injection analysis, and chemical reaction and synthesis. U.S. application Ser. No. 08/671,987, entitled xe2x80x9cHIGH THROUGHPUT SCREENING ASSAY SYSTEMS IN MICROSCALE FLUIDIC DEVICESxe2x80x9d, filed on Jun. 28, 1996 by J. Wallace Parce et al., and assigned to the present assignee, discloses wide ranging applications microfluidic systems in rapidly assaying large number of compounds for their effects on chemical, and preferably, biochemical systems. The phrase, xe2x80x9cbiochemical systemxe2x80x9d, generally refers to a chemical interaction which involves molecules of the type generally found within living organisms. Such interactions include the full range of catabolic and anabolic reactions which occur in living systems including enzymatic, binding, signaling and other reactions. Biochemical systems of particular interest include, e.g., receptor-ligand interactions, enzyme-substrate interactions, cellular signaling pathways, genetic analysis, transport reactions involving model barrier systems (e.g., cells or membrane fractions) for bio-availability screening, and a variety of other general systems.
Many chemical or biological systems also benefit from control over processing parameters such as temperature, concentration of reagents, buffers, salts and other materials, and the like. In particular, some chemical or biological systems require processes to be carried out at controlled and/or controllably varied temperature. In providing such a controlled temperature in miniaturized fluidic systems, external heating elements have generally been used. Such heating elements typically include external resistive heating coils or material, which provide heat to the fluidic system in a conductive manner. This heating unit attaches itself directly to an external portion of the chip to globally heat the chip and to provide a uniform temperature distribution to be present on the chip. This external heating unit, however, is cumbersome. It also complicates chip manufacturing and often affects quality and reliability of the chip. Additionally, the external heating element can fail and generally cannot effectively control heat supplied to the chip, which can cause undesirable temperature gradients and fluctuations in the chip. Accordingly, the external heating element applied to a chip is limited and can be unreliable in controlling process temperature in the chip.
Larger scale temperature controllers have also been used to control reaction temperatures within a reaction vessel, including, e.g., hot-plates, water baths, and the like. Such controllers are not well suited to providing accurate control of temperature within a microfluidic system. In fact, such global heating systems heat the entire material region of the microfluidic device and cannot be used to selectively apply heat to specific regions of the microfluidic device, e.g., specific channels or chambers. Additionally, these large temperature controllers, e.g., hot plates, often require large heating elements, which transfer heat via conduction. These heating elements possess a large characteristic response time, which often relates to a long time to heat or cool material within a reaction vessel in contact therewith in some applications.
Various strategies have been proposed for providing heating in a microscale (such as microfluidic) device. Among these strategies, three of particular interest to the present invention are (1) Joule (or electrolytic) heating, (2) in-channel resistive heating, and (3) proximal resistive heating. In each of these types of heating, an electric signal is used to provide energy. In Joule heating, the electric signal is passed directly through the sample to be heated (which generally must be an electrolytic material, thus the alternative name electrolytic heating.) Electrical energy is converted to heat as it passes through the sample. In resistive heating, a separate conductor (such as a metal or semiconductor channel) is used to carry the electric signal. The impedance and/or resistance of this separate conductor causes the conductor to heat due to electric signal flow. This heat is then transferred by heat conduction to a sample in a microscale device channel or region. In in-channel resistive heating, one or more heating elements is placed in the channel, possibly in contact with the sample material. In proximal resistive heating, one or more heating elements is placed near the channel.
Various of the above general types of heating strategies has been proposed using either DC electrical signals or AC electrical signals. It has also been proposed to detect effects of heating (such as the temperature) or other effects using conductance or impedance of the applied electrical signal. However, there is a continuing need for refined and improved techniques for effecting and/or detecting heating or other parameters in microscale devices. A number of earlier patents discuss various aspects related to the operation and/or construction of microfluidic systems. An example of these include U.S. Pat. No. 5,965,410 (Electrical current for controlling fluid parameters in microchannels); U.S. Pat. No. 5,779,868; U.S. Pat. No. 5,800,690; U.S. Pat. No. 6,306,590; and U.S. Pat. No. 6,171,850 (Integrated devices and systems for performing temperature controlled reactions and analyses).
According to the present invention, two different signals are used one signal to provide energy for heating (or, in alternative embodiments, effecting other parameters) and another signal at a different frequency used as a probe to measure the effect on the parameter. The second signal, in specific embodiments, is an electrical signal having a different frequency than the signal used for heating. Thus, in specific embodiments, the invention provides a mechanism that allows a detection or probe signal to remain separated from an effector signal without requiring physically separate conductive paths.
Specific embodiments according to the invention include (1) a joule heating system and/or method wherein the effector signal and probe signal are signals through an electrolytic sample medium (2) an in-channel resistive heating system and/or method wherein the effector signal and probe signal are signals through an in-channel electrical conductor; and (3) a proximal resistive heating system and/or method wherein the effector signal and probe signal are signals through an electrical conductor proximal to a channel. Specific embodiments according to the invention also include (1) a heating system and/or method wherein the effector signal is a DC signal and the probe signal is a distinguishable AC, e.g. of about 10 Hz; and (2) a heating system and/or method wherein the effector signal is a higher frequency AC signal and the probe signal is a distinguishable lower frequency AC signal.
While various combinations of the above characteristics are possible, according to specific embodiments of the invention a DC heating signal is generally not used when the signal passes through the sample (joule heating).
In various embodiments, the present invention can be embodied in a microfluidic system. In particular, such a system comprises a substrate having at least a first fluid-filled (as used herein, fluid also includes a gel) microscale channel disposed therein. The system also includes a means for generating or receiving the first and second signals for controlling temperature of the fluid in the first portion of the channel.
In a related aspect, the present invention provides a microfluidic system having one or more thermal elements included therein. The system comprises a first channel defined in a substrate, where the channel includes a first end and a second end. A first energy source is provided coupled between the first end and the second end of the channel. The first energy source is applied such that a portion of said material is heated in a portion of said first capillary channel.
A second energy source is also provided coupled to the fluid in the first channel, whereby a signal from the second energy source can be monitored to measure a characteristic of the channel and/or material therein. In further embodiments, this measurement can be used to control adjustment of parameters in the fluid. Typically, a third energy source can also be provided coupled to the channel, whereby a signal from the third energy source is further set at a current or voltage such that a fluid is pumped through said first channel.
In still another related aspect, the present invention provides a microfluidic system, that comprises a capillary channel comprising a first end and a second end, and at least two signal (e.g., energy) sources (or a single source divided or filtered to provide at least two different signals) coupled between the first end and the second end. The source(s) provide voltage and/or current signals coupled to the channel and/or material such that a portion of a fluid is heated in a portion of the capillary channel using one signal and such that parameters, such as temperature, are measured by a second signal.
In a further related aspect, the present invention provides a microfluidic system, which comprises a capillary channel defined in a substrate, the channel comprising fluid therein, wherein the capillary channel has a region whereupon fluid in the region is selectively heated using a voltage bias applied to the fluid in the capillary channel, with temperature measured using a second signal applied to the fluid in the capillary channel.
In a further related aspect, the present invention also provides a multi-port, microfluidic device, which comprises a substrate having a first fluid-filled channel region defined therein. The substrate includes at least a first port and a second port for transporting a material therebetween, and a second channel region defined in the substrate for applying electric current for heating fluid between the first and second ports and for applying a signal for measuring temperature in the fluid.
The present invention also provides a computer program product for operating a microfluidic system in accordance with other aspects of the present invention. In particular, the computer program comprises a computer readable memory including a code that directs an energy source to adjust an electric current or voltage to a channel comprising a fluid therein, to heat the fluid to a selected elevated level and for measuring temperature using a second applied electrical signal.
The present invention also provides methods of controlling temperatures in microfluidic systems as herein described.
Aspects of one illustrative embodiment of a the invention is described below as it might be implemented on a general purpose computer using a suitable programming language such as Java, C++, Cobol, C, Pascal, Fortran., PL 1, LISP, assembly, etc. In the interest of clarity, not all features of an actual implementation are described in this specification. It will be understood that in the development of any such actual implementation (as in any software development project), numerous implementation-specific decisions must be made to achieve the developers"" specific goals and subgoals, such as compliance with system- and business-related constraints, which will vary from one implementation to another. Moreover, it will be appreciated that such a development effort might be complex and time-consuming, but would nevertheless be a routine undertaking of software engineering for those of ordinary skill having the benefit of this disclosure.
Other Features and Benefits
The invention and various specific aspects and embodiments will be better understood with reference to the following drawings and detailed descriptions. In different figures, similarly numbered items are intended to represent similar functions within the scope of the teachings provided herein. In some of the drawings and detailed descriptions below, the present invention is described in terms of the important independent embodiment of a microfluidic device or system. This should not be taken to limit the invention, which, using the teachings provided herein, can be applied to other situations in which it is desired to control the heating of fluids. For purposes of clarity, this discussion refers to devices, methods, and concepts in terms of specific examples. However, the invention and aspects thereof may have applications to a variety of types of devices and systems. It is therefore intended that the invention not be limited except as provided in the attached claims.
Furthermore, it is well known in the art that logic and/or electronic systems and methods such as described herein can include a variety of different components and different functions in a modular fashion. Different embodiments of the invention can include different mixtures of elements and functions and may group various functions as parts of various elements. For purposes of clarity, the invention is described in terms of systems that include many different innovative components and innovative combinations of innovative components and known components. No inference should be taken to limit the invention to combinations containing all of the innovative components listed in any illustrative embodiment in this specification. The functional aspects of the invention that are implemented on a computer, as will be understood from the teachings herein, may be implemented or accomplished using any appropriate implementation environment or programming language, such as C, C++, Cobol, Pascal, Java, Java-script, HTML, XML, dHTML, assembly or machine code programming, etc. All references, publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.